Impact of Aging on Oxysterol Regulation of Alveolar Macrophage Function during S. pneumoniae

衰老对肺炎链球菌期间肺泡巨噬细胞功能的氧甾醇调节的影响

• 批准号: 10737015
• 负责人: Heather Winona Stout Delgado
• 金额: $ 65.99万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737015
• 关键词: 25-hydroxycholesterol; Acute Respiratory Distress Syndrome; Adhesions; Adopted; Adoptive Transfer; Adult; Age; Aging; Agreement; Alveolar; Alveolar Macrophages; Anti-Inflammatory Agents; Biological Assay; Cell physiology; Cells; Cessation of life; Cholesterol; Cholesterol Homeostasis; Clinical; Communicable Diseases; Data; Defect; Development; Environment; Enzymes; Epithelial Cells; Feedback; Growth Factor; Homeostasis; Host Defense; Human; Immune; Immune response; Immune signaling; Immunologics; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Link; Liquid substance; Lung; Macrophage; Macrophage Activation; Mediating; Metabolic; Metabolism; Metagenomics; Microbe; Mitochondria; Mixed Function Oxygenases; Modeling; Molecular; Mus; Patients; Phagocytosis; Phenotype; Plasma; Play; Pneumococcal Infections; Process; Production; Publishing; Pulmonary Pathology; Regulation; Resolution; Respiratory System; Role; Severities; Severity of illness; Signal Transduction; Streptococcus pneumoniae; Structure of parenchyma of lung; Techniques; Testing; Tissues; Work; age related; aged; cell injury; cell type; cytokine; design; ds-DNA; endoplasmic reticulum stress; experimental study; healing; injured; innovation; insight; lipid metabolism; lung injury; metagenomic sequencing; novel; overexpression; oxidation; recruit; response; response to injury; surfactant; tissue injury; tool; transcriptomics

Project Abstract Normal lung aging is associated with multiple structural and functional changes in the respiratory tract. Alveolar macrophages (AM) are long-lived tissue resident innate immune cells of the airways and during steady state conditions, adopt a pro-healing, anti-inflammatory phenotype to maintain lung integrity. AM are key effectors of recognition, initiation, and resolution of the host defense against microbes and play an essential role in mediating host responses to Streptococcus pneumoniae (S. pne). Cell essential and macrophage aged death and the effective clearance of dying cells are processes t hat maintain tissue homeostasis. When efferocytosis is defective, increased tissue injury development of acute respiratory distress syndrome (ARDS) can occur. Despite defects in alveolar phagocytosis being prevalent i n aging, very little is known on how the process of aging and the lung microenvironment contribute to these changes.Our published findings illustrate that an age- associated increase in mitochondrial and endoplasmic reticulum stress during S. pne contributed to dysregulated, overly heightened pro-inflammatory immune responses in AM and lung. To better understand the metabolic factors that might contribute to this phenotype, we examined changes in lipid metabolism in young and aged lung. We observed a molecular reprogramming in response to dysregulated cholesterol homeostasis. Given these findings, we hypothesize that an age-associated increase in lipid metabolism alters innate immune responsiveness and efferocytosis by AMs, thereby contributing to heightened inflammation and prolonged tissue injury in response to S. pne. To test this hypothesis, we have designed three specific aims that will utilize innovative techniques to spatially landscape landscape the mediated utilize the will the resolve single-cell data that will allow us to develop a biologically interpretable of lung pathology from a structural, immunological, and clinical standpoint. This spatial single-cell will enable the pathophysiological characterization of the lung from its macroscopic presentation to single-cell, providing an important basis for the understanding of lipid metabolism on alveolar macrophage process and will provide insights into age-associated changes in lung pathology. In addition, we will metagenomic sequencing of human plasma to distinguish infection and infectious disease, and to assess severity of pneumococcal disease. We firmly believe that fundamental insights gained from this novel assay be applicable to other infection models and will help clarify many of the long-outstanding questions regarding role of aging on specific tissue responses.

项目摘要 正常的肺衰老与呼吸道的多种结构和功能变化有关。肺泡 巨噬细胞 (AM) 是气道中长寿命组织驻留的先天免疫细胞，处于稳定状态 条件下，采取促愈合、抗炎表型以维持肺部完整性。 AM 是关键效应器 识别、启动和解决宿主对微生物的防御，并在介导中发挥重要作用 宿主对肺炎链球菌（S.pne）的反应。细胞 基本的 和 巨噬细胞 老年的 死亡和垂死细胞的有效清除是 维持组织稳态的过程。当胞吞作用有缺陷时，组织损伤就会增加 可能会发生急性呼吸窘迫综合征（ARDS）。尽管肺泡有缺陷 吞噬作用在衰老过程中普遍存在，但人们对衰老过程和吞噬作用的机制知之甚少。 肺部微环境促成了这些变化。我们发表的研究结果表明，年龄 S. pne期间线粒体和内质网应激的相关增加导致失调， AM 和肺部的促炎免疫反应过度增强。为了更好地了解新陈代谢 为了确定可能导致这种表型的因素，我们检查了年轻人和老年人脂质代谢的变化 肺。我们观察到针对胆固醇稳态失调的分子重编程。给定 根据这些发现，我们假设与年龄相关的脂质代谢增加会改变先天免疫 AMs 的反应性和胞吞作用，从而导致炎症加剧和组织延长 对 S. pne 的伤害。为了检验这一假设，我们设计了三个具体目标 空间创新技术 景观 景观 这 介导的 利用 这 将要 这 解析单细胞数据，这将使我们能够开发出生物学上可解释的 从结构、免疫学和临床的角度研究肺部病理学。这个空间单细胞 将使肺的病理生理学特征从宏观表现到 单细胞，为了解肺泡巨噬细胞脂质代谢提供重要基础 过程并将提供对肺部病理学与年龄相关的变化的见解。此外，我们将 对人血浆进行宏基因组测序，以区分感染和传染病，并评估 肺炎球菌疾病的严重程度。我们坚信从这种新颖的测定中获得的基本见解 适用于其他感染模型，并将有助于澄清许多长期悬而未决的问题 衰老对特定组织反应的作用。